Low therapeutic effects of a number of cancer vaccine/immunogenic compositions are thought to be caused by various immunosuppressive elements in the tumor microenvironment, which limit the frequency and functions of induced T cells. Tumor cells themselves are not fully responsible for the immunosuppressive microenvironment. Most epithelial-derived cancers require the support of mesenchymal-derived stromal cells, which are key regulators of tumorigenesis by suppressing the immune control of tumor growth and stimulating angiogenesis, cancer cell proliferation and invasion. The specific CD8+ T cell responses against tumor antigens can be severely dampened by the prevalence of immunosuppressive receptors expressed on certain cancer cells, e.g., melanoma cells. In addition, tumor cells are capable of evading the immune pressure exerted by vaccine composition-induced immune responses due to the advantageous growth of non-targeted subpopulations, further impairing the vaccine/immunogenic composition's efficacy.
For example, melanoma is the most aggressive and lethal form of skin cancer that arises from transformed melanocytes. The incidence of melanoma has been increasing at a steady rate over the last 8 decades, and its death rate continues to rise. Melanoma causes about 75% of skin cancer-related deaths. In the early stages melanoma can be cured by surgical resection, but once it progresses to the metastatic stage, it is extremely hard to treat and largely refractory to current therapies3. The median survival of patients with stage IV melanoma is less than 1 year.
Although promising clinical responses to the two most commonly used therapeutic methods against metastatic melanoma, i.e., chemotherapy and immunotherapy, have been seen in some patients, no therapy has been shown in a phase III trial to improve overall survival in patients with metastatic melanoma. Melanoma vaccine compositions have taken a variety of shapes and forms, ranging from whole-cell tumor preparations to recombinant viral vectors, etc. Although different types of melanoma vaccine composition candidates can induce circulating tumor antigen-specific T cells or lead to some improvement in symptoms, the clinical response rate is only in the range of 5% to 10%. However, the overall therapeutic effect of current vaccine/immunogenic composition strategies in humans is limited. Multiple factors, particularly various immunosuppressive elements in the tumor, contribute to the poor success rate of melanoma vaccine compositions. The supporting stroma of melanoma contains an abundance of tumor stromal fibroblasts (TAFs), which support melanoma growth and metastasis. It has been observed that tumor-infiltrating T cells (TILs) are defective in production of cytokines and lytic enzymes while functional antigen-specific T cells can be found in the blood of cancer patients. Another factor limiting the vaccine/immunogenic composition's efficacy is immune escape. Tumor cells are capable of evading the immune pressure exerted by vaccine/immunogenic composition due to the advantageous growth of antigen-loss variants or non-targeted subpopulations.